Histopathological Assessment of Calcification and Inflammation of Calcific Aortic Valves from Patients with and Without Diabetes Mellitus

Overview

Journal Histol Histopathol

Specialties Anatomy & Histology
Pathology

Date 2016 Jun 30

PMID 27353274

Citations 22

Authors

Josephin Mosch

Christian A Gleissner

Simon Body

Elena Aikawa

Affiliations

Soon will be listed here.

Abstract

Background: Calcific aortic valve disease (CAVD) is the most common valvular heart disease and likely evolves from inflammatory pre-conditions in the valve. Type II diabetes mellitus (DMII) has been associated with pathogenesis of CAVD, however, the mechanism initiating CAVD in DMII is not well understood and the human valve pathology in DMII has not been described. We therefore performed quantitative histological analyses of aortic valves of CAVD patients with and without DMII.

Methods: CAVD human aortic valves (n=45) obtained after surgical valve replacement were examined macroscopically with gross measurements of calcified areas. Inflammation and calcification were assessed by immunohistochemistry and immunofluorescence staining.

Results: Calcification was increased in diabetic patients according to gross measurements (p<0.01) and alizarin red staining (p=0.05). Early calcification markers, including Runx2 (p=0.02) and alkaline phosphatase (ALP, p=0.03) were significantly elevated in diabetic patients. Furthermore, in diabetic patients we found significantly increased expression of annexin II (p=0.04) and annexin V (p=0.04), both of which are thought to play a role in microcalcification formation via apoptosis or extracellular vesicle release. Macrophage numbers were comparable in both groups (p=0.41), while the expression of the pro-inflammatory protein S100A9 (p<0.01) was significantly decreased in diabetic individuals. Evaluation of lymphocytes revealed similar CD8 (p=0.45) and CD4 (p=0.92) T cell counts in diabetic and non-diabetic aortic valves.

Conclusion: Aortic valves from diabetic patients show more calcification, while inflammation is similar in both patient populations. Considering the generally accepted theory of an inflammation-dependent mechanism of calcification, these data suggest that in patients with CAVD requiring valve replacement, diabetic patients could be molecularly in a more advanced disease stage with a higher grade of mineralization than non-diabetic patients.

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References

Gerke V, Creutz C, Moss S . Annexins: linking Ca2+ signalling to membrane dynamics. Nat Rev Mol Cell Biol. 2005; 6(6):449-61. DOI: 10.1038/nrm1661. View

Esser N, Legrand-Poels S, Piette J, Scheen A, Paquot N . Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes. Diabetes Res Clin Pract. 2014; 105(2):141-50. DOI: 10.1016/j.diabres.2014.04.006. View

Chan K, Teo K, Dumesnil J, Ni A, Tam J . Effect of Lipid lowering with rosuvastatin on progression of aortic stenosis: results of the aortic stenosis progression observation: measuring effects of rosuvastatin (ASTRONOMER) trial. Circulation. 2010; 121(2):306-14. DOI: 10.1161/CIRCULATIONAHA.109.900027. View

Gleissner C, Galkina E, Nadler J, Ley K . Mechanisms by which diabetes increases cardiovascular disease. Drug Discov Today Dis Mech. 2008; 4(3):131-140. PMC: 2504760. DOI: 10.1016/j.ddmec.2007.12.005. View

Olsson M, Dalsgaard C, Haegerstrand A, Rosenqvist M, Ryden L, Nilsson J . Accumulation of T lymphocytes and expression of interleukin-2 receptors in nonrheumatic stenotic aortic valves. J Am Coll Cardiol. 1994; 23(5):1162-70. DOI: 10.1016/0735-1097(94)90606-8. View

Rety S, Sopkova J, Renouard M, Osterloh D, Gerke V, Tabaries S . The crystal structure of a complex of p11 with the annexin II N-terminal peptide. Nat Struct Biol. 1999; 6(1):89-95. DOI: 10.1038/4965. View

Yan L, Hofmann Bowman M . Chronic sustained inflammation links to left ventricular hypertrophy and aortic valve sclerosis: a new link between S100/RAGE and FGF23. Inflamm Cell Signal. 2015; 1(5). PMC: 4465803. DOI: 10.14800/ics.279. View

Green A, Ramey D, Emneus M, Iachina M, Stavem K, Bolin K . Incidence of cancer and mortality in patients from the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial. Am J Cardiol. 2014; 114(10):1518-22. DOI: 10.1016/j.amjcard.2014.08.016. View

Bouma G, Lam-Tse W, Wierenga-Wolf A, Drexhage H, Versnel M . Increased serum levels of MRP-8/14 in type 1 diabetes induce an increased expression of CD11b and an enhanced adhesion of circulating monocytes to fibronectin. Diabetes. 2004; 53(8):1979-86. DOI: 10.2337/diabetes.53.8.1979. View

10.

Morrow D, Wang Y, Croce K, Sakuma M, Sabatine M, Gao H . Myeloid-related protein 8/14 and the risk of cardiovascular death or myocardial infarction after an acute coronary syndrome in the Pravastatin or Atorvastatin Evaluation and Infection Therapy: Thrombolysis in Myocardial Infarction (PROVE IT-TIMI 22).... Am Heart J. 2007; 155(1):49-55. PMC: 2645040. DOI: 10.1016/j.ahj.2007.08.018. View

11.

Wallby L, Janerot-Sjoberg B, Steffensen T, Broqvist M . T lymphocyte infiltration in non-rheumatic aortic stenosis: a comparative descriptive study between tricuspid and bicuspid aortic valves. Heart. 2002; 88(4):348-51. PMC: 1767380. DOI: 10.1136/heart.88.4.348. View

12.

Wu H, Maurer M, Friedman R, Marboe C, Ruiz-Vazquez E, Ramakrishnan R . The lymphocytic infiltration in calcific aortic stenosis predominantly consists of clonally expanded T cells. J Immunol. 2007; 178(8):5329-39. DOI: 10.4049/jimmunol.178.8.5329. View

13.

Sarwar N, Gao P, Kondapally Seshasai S, Gobin R, Kaptoge S, Di Angelantonio E . Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet. 2010; 375(9733):2215-22. PMC: 2904878. DOI: 10.1016/S0140-6736(10)60484-9. View

14.

Seok J, Warren H, Cuenca A, Mindrinos M, Baker H, Xu W . Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc Natl Acad Sci U S A. 2013; 110(9):3507-12. PMC: 3587220. DOI: 10.1073/pnas.1222878110. View

15.

Shanahan C, Crouthamel M, Kapustin A, Giachelli C . Arterial calcification in chronic kidney disease: key roles for calcium and phosphate. Circ Res. 2011; 109(6):697-711. PMC: 3249146. DOI: 10.1161/CIRCRESAHA.110.234914. View

16.

Gleissner C . The vulnerable vessel. Vascular disease in diabetes mellitus. Hamostaseologie. 2015; 35(3):267-71. DOI: 10.5482/HAMO-14-11-0059. View

17.

Rajamannan N . Calcific aortic stenosis: lessons learned from experimental and clinical studies. Arterioscler Thromb Vasc Biol. 2008; 29(2):162-8. PMC: 2774235. DOI: 10.1161/ATVBAHA.107.156752. View

18.

Briand M, Lemieux I, Dumesnil J, Mathieu P, Cartier A, Despres J . Metabolic syndrome negatively influences disease progression and prognosis in aortic stenosis. J Am Coll Cardiol. 2006; 47(11):2229-36. DOI: 10.1016/j.jacc.2005.12.073. View

19.

Taylor C, Levenson R . Quantification of immunohistochemistry--issues concerning methods, utility and semiquantitative assessment II. Histopathology. 2006; 49(4):411-24. DOI: 10.1111/j.1365-2559.2006.02513.x. View

20.

Otto C . Valvular aortic stenosis: disease severity and timing of intervention. J Am Coll Cardiol. 2006; 47(11):2141-51. DOI: 10.1016/j.jacc.2006.03.002. View